EP1813616B1 - Pyrazoloquinolines avec activité immunomodulatrice - Google Patents

Pyrazoloquinolines avec activité immunomodulatrice Download PDF

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Publication number
EP1813616B1
EP1813616B1 EP07102257A EP07102257A EP1813616B1 EP 1813616 B1 EP1813616 B1 EP 1813616B1 EP 07102257 A EP07102257 A EP 07102257A EP 07102257 A EP07102257 A EP 07102257A EP 1813616 B1 EP1813616 B1 EP 1813616B1
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Prior art keywords
methyl
radical
phenyl
methoxy
formula
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English (en)
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EP1813616A3 (fr
EP1813616A2 (fr
Inventor
Lars Olof Göran Pettersson
Dorthe Da Graca Thrige
Ian Richard Matthews
Thomas Stephen Coulter
Chiara Ghiron
Chris James Brennan
Muhammed Kamal Uddin
Philip Huxley
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Active Biotech AB
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Active Biotech AB
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Priority claimed from SE0203471A external-priority patent/SE0203471D0/xx
Priority claimed from SE0301299A external-priority patent/SE0301299D0/xx
Priority claimed from SE0301851A external-priority patent/SE0301851D0/xx
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Publication of EP1813616A2 publication Critical patent/EP1813616A2/fr
Publication of EP1813616A3 publication Critical patent/EP1813616A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel heterocyclic compounds, to methods for their preparation, to compositions containing them, and to methods and use for clinical treatment of medical conditions which may benefit from immunomodulation, including rheumatoid arthritis, multiple sclerosis, diabetes, asthma, transplantation, systemic lupus erythematosis and psoriasis. More particularly the present invention relates to novel heterocyclic compounds, which are CD80 antagonists capable of inhibiting the interactions between CD80 and CD28.
  • the immune system possesses the ability to control the homeostasis between the activation and inactivation of lymphocytes through various regulatory mechanisms during and after an immune response. Among these are mechanisms that specifically inhibit and/or turn off an immune response.
  • the T-cells become properly activated only in the presence of additional co-stimulatory signals.
  • additional co-stimulatory signals there is no lymphocyte activation and either a state of functional inactivation termed anergy or tolerance is induced, or the T-cell is specifically deleted by apoptosis.
  • One such co-stimulatory signal involves interaction of CD80 on specialised antigen-presenting cells with CD28 on T-cells, which has been demonstrated to be essential for full T-cell activation. ( Lenschow et al. (1996) Annu. Rev. Immunol., 14, 233-258 )
  • the invention also includes a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising a compound of formula (I) or a pharmaceutically or veterinarily acceptable salt thereof together with a pharmaceutically or veterinarily acceptable excipient or carrier.
  • alkylene refers to a straight or branched alkyl chain having two unsatisfied valencies, for example -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH(CH 2 CH 3 )CH 2 CH 2 CH 3 , and -C(CH 3 ) 3 .
  • Some compounds of the invention contain one or more chiral centres because of the presence of asymmetric carbon atoms.
  • the presence of asymmetric carbon atoms gives rise to stereoisomers or diastereoisomers with R or S stereochemistry at each chiral centre.
  • the invention includes all such stereoisomers and diastereoisomers and mixtures thereof.
  • Salts of salt forming compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates; and base addition salts, for example sodium, potassium, magnesium, and calcium salts.
  • physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates
  • base addition salts for example sodium, potassium, magnesium, and calcium salts.
  • quaternary amino salts are also feasable, and are included in the invention.
  • R 4 groups include those present in the compounds of the Examples herein.
  • compounds of the invention may be prepared by synthetic methods known in the literature, from compounds which are commercially available or are accessible from commercially available compounds.
  • Tin (II) chloride dihydrate (12.5 g, 0.055 mol) was added in one portion to a stirred solution of 2-(4-nitrophenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (intermediate 1) (3.59 g, 0.011 mol) in ethyl alcohol (110 ml) at room temperature. The mixture was then heated to 80 °C for 8 h, cooled to room temperature and filtered to leave a yellow solid.
  • Examples 8 to 28 were also prepared by the method of Example 1 using the appropriate acid chloride:
  • europium and allophycocyanin are associated with CD28 and CD80 indirectly (through antibody linkers) to form a complex, which brings the europium and APC into close proximity to generate a signal.
  • the complex comprises the following six proteins: fluorescent label 1, linker antibody 1, CD28 fusion protein, CD80 fusion protein, linker antibody 2, and fluorescent label 2. The table below describes these reagents in greater detail.
  • Fluorescent label 1 Anti-Rabbit IgG labelled with Europium (1 ⁇ /ml) Linker antibody 1 Rabbit IgG specific for mouse Fc fragment (3 ⁇ g/ml) CD28 fusion protein CD28 - mouse Fc fragment fusion protein (0.48 ⁇ g/ml) CD80 fusion protein CD80 mouse Fab fragment (C215) fusion protein (1.9 ⁇ g/ml) Linker antibody 2 G ⁇ M ⁇ -biotin: biotinylated goat IgG specific for mouse kappa chain (2 ⁇ g/ml) Fluorescent label 2 SA-APC: streptavidin labelled allophycocyanin (8 ⁇ g/ml)
  • Non-specific interaction was measured by substituting a mouse Fab fragment (C215) for the CD80 mouse Fab fragment fusion protein (1.9 ⁇ g/ml).
  • the assay was carried out in black 384 well plates in a final volume of 30 ⁇ l.
  • Assay buffer 50mM Tris-HCl, 150mM NaCl pH7.8, containing 0.1% BSA (w/v) added just prior to use.
  • the EC 50 results for the compounds of Examples 15, 21, 29 and 35 were 8 ⁇ M, 1.9 ⁇ M, 950 nM and 148nM respectively.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hematology (AREA)
  • Neurology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (4)

  1. Composé de formule (I) ou sel acceptable du point de vue pharmaceutique ou vétérinaire de celui-ci :
    Figure imgb0048
     dans lequel
    R1 est H, F, Cl ou un groupe méthyle ou méthoxy ;
    R2 est H ou un groupe méthyle, méthoxy, cyclopropyle, phényle ou phényle substitué par fluoro, chloro, méthyle ou méthoxy ;
    R3 est H, F, Cl ou un groupe méthyle, méthoxy ou méthylènedioxy ;
    Y est -O-, -S- ou -N(R5) où R5 représente H ou un groupe méthyle ;
    X est une liaison ou un radical -CH2- ou -CH2CH2- ; et
    R4 représente -NR7C(=O)R6, -NR7C(=O)OR6, -NHC(=O)NHR6 ou -NHC(=S)NHR6 et dans ceux-ci
    R6 est H ou un radical de formule -Alkb-Q dans lequel
    b vaut O ou 1,
    Alk est un radical -(CH2)n-, -CH((CH2)mCH3)-(CH2)n-, -CH((CH2)CH3)(CH2)p(CH3)-(CH2)n-, -(CH2)n-(O-(CH2) ou -(CH2)n-O-(CH2)n-O-(CH2)m-, où
    n vaut 1, 2, 3 ou 4 et
    m et p valent chacun indépendamment 0, 1, 2, 3 ou 4, et
    Q représente H, -OH, -COOCH3 ou un groupe phényle, cyclopropyle, cyclopentyle, cyclohexyle, pyridyle, furyle, thiényle ou oxazolyle ; et
    R7 est H ou,
    lorsqu'ils sont pris conjointement avec l'atome d'azote auquel ils sont attachés, R6 et R7 forment un cycle pyrrolidin-2-one ou pyrrolidine-2,5-dione,
    à condition que lorsque Y est -NH-, R2 est H, R3 est H et X est une liaison alors R4 ne soit pas un groupe (alkyl en C1-C4)carbamoylamino.
  2. Composé selon la revendication 1 dans lequel
    R1 est H, F ou Cl ;
    R2 est H ;
    R3 est H, F ou Cl ;
    Y est -NH- ;
    X est une liaison ; et
    R4 représente -NR7C(=O)R6, -NR7C(=O)OR6 ou -NHC(=O)NHR6 dans lesquels :
    R6 est H ou un radical de formule -Alkb-Q dans lequel
    b vaut 0 ou 1,
    Alk est un radical -(CH2)n-, -CH((CH2)mCH3)-(CH2)n-, -CH((CH2)mCH3)-((CH2)pCH3)-(CH2)n-, -(CH2)n-O-(CH2)m- ou -(CH2)n-O-(CH2)n-O-(CH2)m-, où
    n vaut 1, 2, 3 ou 4 et
    m et p valent chacun indépendamment 0, 1, 2, 3 ou 4, et
    Q représente H, -OH, -COOCH3 ou un groupe phényle, cyclopropyle, cyclopentyle, cyclohexyle, pyridyle, furyle, thiényle ou oxazolyle ; et
    R7 est H ou,
    lorsqu'ils sont pris conjointement avec l'atome d'azote auquel ils sont attachés, R6 et R7 forment un cycle pyrrolidin-2-one ou pyrrolidine-2,5-dione.
  3. Composé selon la revendication 1 dans lequel
    R1 est F,
    R2 est H ou un groupe cyclopropyle,
    R3 est H,
    X est une liaison et
    R4 est -NHC(=O)NHR6.
  4. Composition pharmaceutique ou vétérinaire comprenant un composé selon l'une quelconque des revendications 1 à 3 conjointement avec un excipient ou véhicule acceptable du point de vue pharmaceutique ou vétérinaire.
EP07102257A 2002-11-22 2003-11-21 Pyrazoloquinolines avec activité immunomodulatrice Expired - Lifetime EP1813616B1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US42824002P 2002-11-22 2002-11-22
SE0203471A SE0203471D0 (sv) 2002-11-22 2002-11-22 Immunomodulatory compunds
SE0301299A SE0301299D0 (sv) 2003-05-06 2003-05-06 Immunomodulatory compounds
US48212203P 2003-06-25 2003-06-25
SE0301851A SE0301851D0 (sv) 2003-06-25 2003-06-25 Immunomodulatory compounds
EP03773026A EP1562944B1 (fr) 2002-11-22 2003-11-21 Pyrazoloquinolines a activite immunomodulatrice

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EP03773026A Division EP1562944B1 (fr) 2002-11-22 2003-11-21 Pyrazoloquinolines a activite immunomodulatrice

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EP1813616A2 EP1813616A2 (fr) 2007-08-01
EP1813616A3 EP1813616A3 (fr) 2007-08-08
EP1813616B1 true EP1813616B1 (fr) 2013-03-27

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EP (2) EP1562944B1 (fr)
JP (1) JP2006509047A (fr)
CN (1) CN100347173C (fr)
AT (1) ATE353898T1 (fr)
AU (1) AU2003279687A1 (fr)
CA (1) CA2506524A1 (fr)
DE (1) DE60311861T2 (fr)
ES (1) ES2282693T3 (fr)
HK (1) HK1086562A1 (fr)
NO (1) NO20053018L (fr)
NZ (1) NZ540081A (fr)
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JP4892338B2 (ja) 2003-03-14 2012-03-07 メディジーン アーゲー 免疫調節複素環化合物
GB0325644D0 (en) 2003-11-04 2003-12-10 Avidex Ltd Immuno ihibitory pyrazolone compounds
PL1776366T3 (pl) 2004-08-09 2009-06-30 Medigene Ag Immunomodulujące oksopirazolocynoliny jako inhibitory CD80
WO2008043072A2 (fr) * 2006-10-05 2008-04-10 Biogen Idec Inc. Antagonistes de cd80 pour le traitement des affections néoplasiques
EP2676666A1 (fr) * 2012-06-20 2013-12-25 Eidgenössische Technische Hochschule Zürich (ETH) Composés destinés à être utilisés dans le diagnostic ou la thérapie de plaques d'athérosclérose vulnérables
CN102977095B (zh) * 2012-12-03 2015-10-28 华东理工大学 吡唑并喹啉类化合物及其用途
BR112015014839B1 (pt) 2012-12-22 2022-09-06 Kbp Biosciences Co., Ltd Forma cristalina do composto utilizado como antagonista do receptor de mineralocorticoide, seus usos, seu processo de preparação e composição farmacêutica
EP2883883A1 (fr) 2013-12-16 2015-06-17 Cardio3 Biosciences S.A. Cibles thérapeutiques et agents utiles dans le traitement des lésions ischémiques de reperfusion
CN110698456B (zh) * 2019-11-06 2021-05-14 重庆医药高等专科学校 一种2,3-二氢硫代色烯-4-酮及其衍生物的合成方法

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JP2006509047A (ja) 2006-03-16
US20050203118A9 (en) 2005-09-15
US20060217411A1 (en) 2006-09-28
ATE353898T1 (de) 2007-03-15
NZ540081A (en) 2008-03-28
US7081456B2 (en) 2006-07-25
EP1813616A3 (fr) 2007-08-08
EP1813616A2 (fr) 2007-08-01
EP1562944B1 (fr) 2007-02-14
DE60311861T2 (de) 2007-11-22
CN100347173C (zh) 2007-11-07
CN1729191A (zh) 2006-02-01
US20040116461A1 (en) 2004-06-17
ES2282693T3 (es) 2007-10-16
HK1086562A1 (en) 2006-09-22
WO2004048378A1 (fr) 2004-06-10
NO20053018D0 (no) 2005-06-20
RU2005119639A (ru) 2006-01-20
US7291612B2 (en) 2007-11-06
EP1562944A1 (fr) 2005-08-17
NO20053018L (no) 2005-08-22
CA2506524A1 (fr) 2004-06-10
RU2328496C2 (ru) 2008-07-10
AU2003279687A1 (en) 2004-06-18

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